Ring-tri-substituted-aniline derivatives



United States Patent 3,133,675 RING-TRI-SUBSTITUTED-ANILINE DERIVATIVES Raymond 0. Clinton, East Greenbush, and Donald F.

Page, North Greenbush, N.Y., assignors to Sterling Drug Inc., New York, N.Y., a corporation of Delaware No Drawing. Filed July 3, 1959, Ser. No 824,784

17 Claims. ((31. 269-2943) This invention relates to compositions of matter of the class of ring-tri-substituted-aniline derivatives, their intermediate nitrobenzenes and to their preparation.

The invention here resides in a composition having a molecular structure in which a primary amino substituent is attached to a benzene ring that is substituted further by lower-hydrocarbyloxy, halo and certain lower-tertiaryamino-(polycarbon-lower-alkoxy) radicals. The invention thus resides in a composition of matter selected from the group consisting of: (a) ring-tri-substituted-anilines in which the substituents are, respectively, a halogen atom, a lower-hydrocarbyloxy radical, and a lower-tertiaryamino-substituted polycarbon-lower-alkoxy radical; and (b) acid addition salts thereof.

Preferable halo-(lower-hydrocarbyloxy)-[lower-tertiaryamino(polycarbon-lower-alkoxy)]-aniline derivatives in free base form have the Formula I (halogen) 0 X--N B where the halogen radical is bromo, chloro, iodo or fluoro, R is a lower-hydrocarbyl radical, X is a polycarbon-loweralkylene radical having its free valence bonds on different carbon atoms and NB is a lower-tertiary-amino radical such as di-(lower-alkyl)-amino, l-piperidyl, (loweralkylated)-1-piperidyl, l-pyrrolidyl and (lower-alkylated)- l-pyrrolidyl radicals. The halo, lower-hydrocarbyloxy and lower-tertiary-amino(polycarbon-lower-alkoxy) substituents can be in any of the available ring-positions relative to each other.

These compounds and their acid addition salt derivatives have high local anesthetic activity and low irritancies. In general, the acute toxicity of these compounds parallels their activity.

Particularly preferred embodiments of our invention are the 3-halo-4[lower-tertiary-amino(polycarbon-loweralkoxy)]-5-(lower-alkoxy)anilines having in free base form the Formula II where X and NB have the meanings designated above, halogen is bromo or chloro, and R is a lower-alkoxy radical.

In the above general Formula II the polycarbon-loweralkylene radical designated as X has preferably from two to four carbon atoms and has its two free valence bonds on dilferent carbon atoms. Thus, preferred embodiments for X include such groups as CH CH CH CH CH l -C aC a) -CH CH CH CH -CH CH(CH )CH and the like. The lower-tertiary-amino radical shown above as NB represents radicals containing only the elements carbon, hydrogen and nitrogen and can contain from two to about twelve carbon atoms. The radical NB comprehends di-(loWer-alkyD-amino radicals where the lower-alkyl groups are alike or different and each alkyl group has preferably one to six carbon atoms, such di-(lower-alkyDamino radicals including dimethylamino, diethylamino, ethylmethylamino, diisopropylamino, ethyln-propylamino, di-n-bntylamino, di-n-hexylamino, and the like. Further, the lower-tertiary-amino radical designated as NB encompasses certain saturated N-heteromonocyclic radicals having five to six ring atoms, illustrated by examples such as l-piperidyl; (lower-alkylated)-1-piperidyl such as Z-methyl-l-piperidyl, 3-ethyl-l-piperidyl, 4-rnethyl-1-piperidyl, 2,6-dimethyl-1-piperidyl, 2-ethyl-3- methyl-l-piperidyl, Z-ethyl-S-methyl-l-piperidyl, 2-methyl- 3-ethyl-1-piperidyl, 4-isopropyl-1-piperidyl, 2-butyl-l-piperidyl, 3-butyl-l-piperidyl, 2-isobutyl-1-piperidyl, 4-isopropyl-l-piperidyl, 2,4,6-trimethy'l l-piperidyl, 2,2, 6-trimethyl-l-piperidyl, 3,4-diethyl-l-piperidyl; l-pyrrolidyl; (lower-alkylated)-l-pyrrolidyl such as Z-methyl-l-pyrrolidyl, 2,5-dimethyl-l-pyrrolidyl, 3-methyl-l-pyrrolidyl, 2-ethyl-1-pyrrolidyl, Z-butyl-l-pyrrolidyl, 2-sec-butyl1- pyrrolidyl, 2-isobutyl-l-pyrrolidyl, 2,4-dimethyl-1-pyrrolidyl, 3,4-diethyl-l-pyrrolidyl, 3-ethyl-2,4-dimethyl-l-pyrrolidyl, 2-ethyl-3,4,5-trimethyl-l-pyrrolidyl, 3-ethyl-2,4,5- trimethyl-l-pyrrolidyl, '2,4-diethyl-3,5-dimethyl-l-pyrrolidyl, 2,2,5,5-tetramethyl-l-pyrrolidyl, 2,5-dimethyl-2,5-diethyl-l-pyrrolidyl, 2,5-dimethyl-2,5-dipropyl-l-pyrrolidyl; and the like. The lower-hydrocarbyl radical R when lower-alkyl has preferably one to eight carbon atoms and comprehends such radicals as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, Z-butyl, n-amyl, isoamyl, Z-amyl, n-hexyl, n-heptyl, n-octyl, and the like.

The compounds of our invention were prepared preferably according to the procedure represented by the following series of equations where halogen, X, NB and R have the meanings given above andHal is chloride, bromide or iodide:

In step 1 a halo-(lower-hydrocarbyloxy)-nitro-phenol (HI) is converted into a halo-[lower-tertiary-amino(polycarbon lower alkoxy)] (lower-hydrocarbyloxy)-nitrobenzene (V) by reaction with a tertiary-aminoalkyl halide (IV). In step 2 the tri-substituted-nitrobenzene (V) is reduced to yield the corresponding tri-substituted aniline (I). A specific illustration of this procedure is the formation of 3-brom0-4-(Z-diethylaminoethoxy)-S-ethoxyaniline by reacting 2-bromo-4-nitro-6-ethoxyphenol, pref erably in the form of an alkali metal salt, with a Z-diethylaminoethyl halide, preferably the chloride, to yield 3 bromo 4 (Z-diethylaminoethoxy)--ethoxynitrobenzene, and reducing this tri-substituted-nitrobenzene to yield the corresponding 3-bromo-4-(2-diethylaminoethoxy) -5-ethoxyaniline.

Step 1 is carried out preferably using a halo-nitro- (lower-hydrocarbyloxy)phenol (III) in the form of a metal derivative, e.g., alkali metal, with a tertiary-aminoalkyl halide (1V). Alternatively, step 1 can be carried out using a halo-nitro-(loWer-hydrocarbyloxy)phenol itself, however, with a resulting decrease in the yield of the tri-substituted-nitrobenzene (V).

The reduction step 2 is carried out preferably by chemical methods or, alternatively, by catalytic hydrogenation although this method is less desirable where the halo substituent is bromo or iodo. Suitable chemical reducing agents include iron and hydrochloric acid, ferrous sulfate and ammonia, tin and hydrochloric acid, sodium hydrosulfite, etc. In practicing our invention, we preferably used iron and hydrochloric acid. Catalysts suitable when catalytic hydrogenation is employed include Raney nickel, platinum, palladium or other catalysts generally effective to catalyze hydrogenation of nitro groups to amino groups.

Step 1 can also be carried out stepwise, that is, by first ,haloalkylating a halo-nitro-(lower-hydrocarbyloxy)phenol (III) to form a halo-ha]oalkoxy-hydrocarbyloxynitrobenzene which is then treated with a secondary amine having the formula HNB. The first step can be accomplished by reacting a halo-nitro-(lower-hydrocarbyloxy) phenol or a metal derivative thereof with a haloalkylating agent, preferably a haloalkyl ester of a strong inorganic acid or an organic sulfonic acid, such as a haloalkyl paratoluenesulfonate, haloalkyl benzenesulfonate, haloalkyl halide, and the like. As illustrations of this stepwise procedure, 2-chloro-4-nitro-6-n-propoxyphenol is haloalkylated by treating its potassium salt with 3-chloropropyl para-toluenesulfonate to form 3-chloro-4-(3-chloropropoxy)-S-n-propoxynitrobenzene which then is treated with dimethylamine or piperidine to form 3-chloro-4-(3- dirnethylaminopropoxy)-5-n-propoxyaniline or 3-chloro- 4-[3-(1-piperidyl)propoxy] -5 n propoxyaniline, respectively.

The intermediate halo-(lower-hydrocarbyloxy)-nitrophenols (III) are generally old, as are various procedures for their preparation. In practicing our invention we prepared these intermeidates where the halo substituent is chloro, bromo or iodo by reacting the corresponding (lower-hydrocarbyloxy)-nitrophenols with a halogenating agent, e.g., bromine, pyridinium bromide perbrornide, sulfuryl chloride, chlorine, iodine monochloride, etc. Alternatively, these halo-(lower-hydrocarbyloxy)-nitrophenols can be prepared by nitrating a halo-(lower-hydrocarbyloxy)-phenol or by other published procedures that are well-known to the chemist (see Examples 1A and 2B). A method of preparing the fluoro-(lower-hydrocarbyloxy)-nitrophenols is afforded by diazotizing an amino- (lower-hydrocarbyloxy)-nitrophenol, reacting the diazonium salt with fiuoroboric acid to form the diazonium fluoroborate, and heating the latter to form the desired fiuoro- (lower-hydrocarbyloxy) -nitrophenol.

Our new halo-(lower-hydrocarbyloxy)-[lower-tertiaryamino(polycarbon-lower-alkoxy)laniline derivatives are useful in the free base form or in the form of acid addition salts, and both forms are within the purview of the invention, and, in fact, are considered to be one and the same invention. The acid addition salts are simply a more convenient form for use; and, in practice, use of the 'salt form inherently amounts to use of the base form.

The acids which can be used to prepare acid addition salts are preferably those which produce, when combined with the free base, pharmacologically acceptable salts, that is, salts whose anions are relatively innocuous to the animal organism in therapeutic doses of the salts, so that the beneficial physiological properties inherent in the free base are not vitiated by side effects ascribable to the anions; in other words, the latter do not substantially affect the pharmacodynamic properties inherent in the cations. In practicing our invention, we found it convenient to employ the hydrochloride salts. However, other appropriate pharmacologically acceptable salts are those derived from mineral acids such as hydrobromic acid, hydriodic acid, nitric acid, phosphoric, sulfamic and sulfuric acid; and organic acids such as acetic acid, citric acid, tartaric acid, lactic acid, quinic acid, methansulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like, giving the hydrobromide, hydriodide, nitrate, phosphate or acid phosphate, sulfamate, sulfate or acid sulfate, acetate, citrate or acid citrate, tartrate or acid tartrate, lactate, quinate, methanesulfonate, ethanesulfonate, benzenesulfonate and p-toluenesulfonate salts, respectively.

Although pharmacologically acceptable salts are preferred, all acid-addition salts are within the scope of the invention. All acid-addition salts are useful as sources of the free base form even if the particular salt per se is not desired as the final product, as for example when the salt is formed only for purposes of purification or identification, or when it is used as an intermediate in preparing a pharmacologically acceptable salt by ion exchange procedures.

The chemical structures of our halo-(lower-hydrocarbyloxy) [lower tertiary -arnino(polycarbon loweralkoxy)]anilines are established by their mode of synthesis and corroborated by the correspondence of calculated and found values for the elementary analyses for representative examples.

The following examples will further illustrate the invention without, however, limiting it thereto.

EXAMPLE 1 A. Halo-Nitro- (Lower-A lk0xy)Phen0ls As noted above, these compounds are generally old and various procedures for their preparation are given in the literature. One of these procedures is the reaction of a ,(lower-alkoxy)-nitrophenol with a halogenating agent. This method is illustrated by the following synthesis of 2-bromo 4-nitro-6-n-propoxyphenol: A solution of 4.9 g. of bromine in ml. of acetic acid was added over a period of four hours to a stirred solution of 5.33 g. of 2-n-propoxy-4-nitrophenol in 40 ml. of acetic acid. The resulting solution was stirred on a steam bath for an additional two and one-half hours. The reaction mixture was then added to an ice-water mixture to yield a solid precipitate. This solid was collected and recrystallized once from ethanol-water and onct from isopropanol to yield 2-brorno-4-nitro-6-n-propoxyphenol, M.P. 116.0- ll8.0 C. (corn).

Analysis.-Calcd. for C H BrNO N, 507; Br, 2894. Found: N, 5.05; Br, 29.03.

The intermediate 2-n-propoxy-4-nitrophenol was prepared from catechol (1,2-dihydroxybenzene) by first dipropylating catechol to form 1,2-di-n-propoxybenzene, nitrating this compound to yield 1,2-di-n-propoxy-4-nitrobenzene and then dealkylating the l-ether; This threestep procedure is given as follows: 1,2-di-n-pr0poxybenzene.-n-Propyl benzenesulfonate, 343.4 g., was added slowly under nitrogen at a temperature range of about 45 to C. to a solution containing 188.9 g. of catechol, 111.5 g. of potassium hydroxide, 650 ml. of ethanol and 215 ml. of water. An additional 13 g. of potassium hydroxide in water was added after the reaction mixture had been refluxed for one hour; refluxing was then con; tinued for a total of twelve hours. To the resulting solution was added 98.5 g. of potassium hydroxide in water,

followed by the slow addition of 343.4 g. of n-propyl benzene-sulfonate. After one hour of refluxing, an additional g. of potassium hydroxide was added, and refluxing was continued for another eleven hours. The cooled mixture was separated and the water layer was extracted with ether. The ether extracts were combined, dried, and the ether removed by distillation in vacuo. Distillation of the residual material yielded 238.4 g. of 1,2-di-n-propoxybenzene, B.P. 142-148 C. at mm. 1,2-di-n-pr0poxy-4-nitrobenzene.-To a solution of 58 ml. of concentrated nitric acid in 220 ml. of acetic acid kept at about 5 to 10 C. was added slowly a solution of 84.3 g. of 1,2-di-n-propoxybenzene in 130 ml. of acetic acid. The reaction mixture was stirred at about 510 C. for about thirty minutes and then allowed to warm up to room temperature over a period of about three and onehalf hours. The mixture was then added to ice-water and the solid that separated was collected and recrystallized from methanol-water to yield 97.2 g. of 1,2-di-npropoxy-4-nitrobenzene, M.P. 62.0-63.2 C. 2-n-propoxy- 4-nitr0phen0l.A reaction mixture containing 29.1 g. of 1,2-di-n-propoxy-4-nitrobenzene, 58 g. of potassium hydroxide, 580 ml. of water and 580 ml. of ethylene glycol monomethyl ether was stirred under reflux for about five days. The mixture was evaporated to dryness in vacuo. About 350 ml. of Water was added and the mixture was again evaporated to dryness. The residual material was suspended in about one liter of water, filtered, and the filtrate was acidified with concentrated hydrochloric acid. The acidic aqueous solution was extracted with ether, the ether extract evaporated by distilling in vacuo and the resulting residual material recrystallized from ethanol-water to yield 22.6 g. of crystalline 2-n-propoxy-4-nitrophenol, M.P. 81.5-82.5 C.

2-chloro-4-nitro-6-n-propoxyphenol is obtained by chlorinating 2-n-propoxy-4-nitrophenol using chlorine as the chlorinating agent following the procedure given in Example 7A for the preparation of 2-chloro-4-nitro-6- methoxy-phenol.

Other halo-nitro-(lower-alkoxy) phenols that can be prepared following the above procedures given for the preparation of the Q-halo-4-nitro-6-n-propoxyphenols using the appropriate reactants are: 2-bromo-4-nitro--n-octoxyphenol by reacting 2-n-octoxy-4-nitrophenol with bromine; 2-nitro-4-bromo-5-isoproproxyphenol by reacting Z-nitro- S-isopropoxyphenol with bromine; 2-bromo-4-n-butoxy-6- nitrophenol by reacting 2-nitro-4-n-butoxyphenol with bromine; 2-n-propoxy-4-bromo-S-nitrophenol by reacting 2-npropoxy-S-nitrophenol with bromine; 2-chloro-4-nitro-5- ethoxyphenol by reacting 3-ethoxy-4-nitrophenol with sulfuryl chloride; 2-iodo-4-nitro-6-n-propoxyphenol by react-.-

ing 2-n-propoxy-4-nitrophenol with iodine monochloride; and the like.

These intermediate halo-nitro-(lower-alkoxy)pheno1s also can be prepared by other known procedures such as nitration of halo-(lower-alkoxy) phenols, e.g., preparation of 2-nitro-3-chloro-5-methoxyphenol by nitrating 3-chloro- S-methoxyphenol (Hodgson and Batty, J. Chem. Soc. 1934, 1433), or reacting a halo-hydroxy-(lower-alkoxy)- benzaldehyde with cold fuming nitric acid, e.g., preparation of 2-nitro-4-bromo-5-methoxyphenol by reacting 2- hydroxy-4-methoxy-5-bromobenzaldehyde with cold fuming nitric acid (Srikantia et al., J. Chem. Soc. 1932, 524), or other procedures. Illustrative of the preparation of a fluoro-nitro-(lower-alkoxy)phenol is the formation of 2- fluoro-4-nitro-d-methoxyphenol by diazotizing -2-amino-4- nitro-6-methoxyphenol, reacting the resulting diazonium salt with fiuoroboric acid to form the corresponding diazonium fluoroborate and heating the fluoroborate to form 2-fluoro-4-nitro-6-methoxyphenol. For other references to the synthesis of halo-nitro-(lower-alkoxy)phenols, see Examples 2A and 2B.

B. Halo-(Lower-Alkoxy)-[Lower-Tertiary-Amino(Polycarb0nL0wer-Alk0xy) l-Nitrobenzenes The preparation of these compounds is illustrated by the following preparation of 3-bromo-4-(2-diethylamino- 6 ethoxy)-5-n-propoxynitrobenzene: A solution of sodium ethoxide was obtained by reacting 0.5 g. of sodium with 20 ml. of absolute ethanol, adding 50 ml. of toluene and removing the excess ethanol by distillation. To this solution was added 6.1 g. of 2-bro1no-4-nitro 6-n-propoxyphenol to convert it into its sodium salt. A solution of 2.98 g. of Z-diethylaminoethyl chloride in 5 0 ml. of toluene was added and the resulting reaction mixture was stirred under reflux for about eighty-seven hours under anhydrous conditions. The solid sodium chloride was filtered, the solvent removed by distilling in vacuo and the residual oily material, 3-bromo 4-(2-diethylaminoethoxy)-5-npropoxynitrobenzene in its free base form, was taken up in ether and treated with excess ethereal hydrogen chloride to yield a light tan solid. This solid was dissolved in water and treated with aqueous potassium carbonate solution. The oily product that separated was taken up in ether and the ether solution treated with an excess of ethereal hydrogen chloride to yield the solid hydrochlo ride. This salt was recrystallized three times from ethanol-ether to yield in purified form, 3-bromo-4(2-diethylaminoethoxy)-5-n-propoxynitrobenzene as its monohydrochloride salt, M.P. 148.6l51.2 C. (corn).

Analysis.Calcd. for C H BrN O .HCl: Cl-, 8.61; N, 6.80. Found: Cl, 8.61; N, 6.63.

Other halo-(lower-alkoxy) [lower-tertia'ry-amino (polycarbon-lower-alkoxy) ]-nitrobenzenes that can be prepared according to the foregoing procedure used for the preparation of 3-bromo-4-(Z-diethylaminoethoxy)-5-n-propoxynitrobenzene using the appropriate halo-(lowenalkoxy)-nitrophenol and loWer-tertiary-amino-(polycarbonlower-alkyl) halide include:

3 -bromo-4- (Z-dimethylaminoethoxy) -5 -n-prop oxynitrobenzene using 2-bromo-4-nitro-6-n-propoxyphenol and Z-dimethylaminoethyl chloride;

3-chloro-4- (2-diethylaminoethoxy) -5-n-propoxynit'robenzene using 2-chloro-4-nitro-6-n-propoxyphenol and 2- diethylaminoethyl bromide;

3-bromo-4-(Z-di-n-butylaminoethoxy) 5-n-propoxynitrobenzene using 2-bromo-4-nitro-6-n-propoxyphenol and Z-di-n-butylaminoethyl iodide;

3 -bromo-4- 4-diethylaminobutoxy) -5 -n-propoxynitrobenzene using 2-bromo-4-n tro-G-n-propoxyphenol and 4- diethylaminobutyl chloride;

3-bromo-4- [2- (N-methyl-N-ethyl -aminoethoxy] -5-npropoxynitrobenzene rusing 2-bromo-4-nitro-6-n-propoxyphenol and Z-(N-methyl-N-ethyl)aminoethyl chloride;

3 -bromo-4- 3 #diethy1amino-2-prop oxy) -5-n-propoxynitrobenzene using 2-bromo-4-nitro-6-n-propoxyphenol and 3-diethylamino-2-propyl chloride;

3-bromo-4- (Z-diethylaminoethoxy) -5-n-octoxynitrobenzene using 2-bromo-4-nitro-6-n-octoxyphenol and 2- diethylaminoethyl chloride;

2- (Z-diethylaminoethoxy) -4-isopropoxy-5 -bromonitrobenzene using 2-nitro-4-bromo-5-isopropoxyphenol and 2-diethylaminoethyl chloride;

2- Z-diethylaminoethoxy) -3-bromo-S-n-butoxynitrobenzene using 2-bromo-4-n-butoxy-6-nitrophenol and 2-diethylaminoethyl chloride;

2-bromo-4-n-propoxy-5- [3-( l-piperidyl) propoxy1nitrobenzene using 2-n-propoxy-4-bromo-5-nitrophenol and 3-( l-piperidyDpropyl chloride;

2-ethoxy-4- [2- B-ethyI-I-piperidyl) ethoxy] -5-ch1oronitrobenzene using 2-chloro-4-nitro-5-ethoxyphenol and 2-(3-ethyl-1-piperidyl)ethyl chloride;

2-chloro-4-methoxy-6- [3- l-pyrrolidyl) propyl] nitrobenzene using 2-nitro-3-chloro-5-methoxyphenol and 3-(1- pyrrolidyDpropyl chloride;

2- [2- (2,5 -dimethyl1 -pyrrolidyl) ethoxy] -4-methoxy-5- 'bromonitrobenzene using 2-nitro-4-bromo-5-methoxyphenol and 2-(2,5-dimethyl-l-pyrrolidyDethyl chloride;

3-iodo-4-(Z-diethylaminoethoxy) -5-n-propoxynitrobenzene using 2-iodo-4-nitro-6-n-propoxyphenol and 2-diethylaminoethyl chloride;

3-fiuoro-4- (Z-diethylaminoethoxy --methoxynitrobenzene using 2-fluoro-4-nitro-6-methoxyphenol and 2-diethylaminoethyl chloride;

3-chloro-4- [2-(Z-methyl-l-piperidyl) ethoxy] -5-methoxynitrobenzene using 2-chloro-4-nitro-6-methoxyphenol and 2-(Z-methyl-l-piperidyl)ethyl chloride;

3-chloro-4-[3-(4-methyl-l-piperidyl)propoxy]-5-ethoxynitrobenzene using 2-chloro-4-nitro-6-ethoxyphenol and 3-(4-methyl-l-piperidyl) propy-l chloride;

'3-brorno-4- [2-(2,6-dimetl1yl-l-piperidyl) ethoxy] -6-eth- '3-chloro-4-[3-(2-methyl-3-ethyl-1-piperidyl)propoxy] -5- ethoxynitrobenzene using 2-chloro-4-nitro-6-ethoxyphenol and 3-(2-methyl-3-ethyl-1-piperidy1)propy1 chloride;

3-ch1oro-4- [2- (4-isopropyl-l-piperidyl) ethoxy]-6-methoxynitrobenzene using 2-chloro-4-nitro-5-methoxyphe nol and 2-(44sopropyl-1-piperidyl)ethyl chloride;

3 -chloro-4- [2- (Z-butyl- 1 -piperidyl ethoxy] -5-rnethoxynitrobenzene using 2-chloro-4-nitro-6-rnethoxyphenol and 2-(2-butyl-1-piperidyl)ethyl chloride;

3-bromo-4-[ 3- 3-butyl- 1-piperidyl)propoxy] -5-ethoxy-nitrobenzene using 2-bromo-4-nitro-6-ethoxyphenol and 3-(3-butyl-1-piperidyl)propyl chloride;

3-bromo-4-[2-(2-isobutyl-l-piperidyl)ethoxy1-5-methoxynitrobenzene using 2-bromo-4-nitro-6-methoxyphe- 1101 and 2-(Z-isobutyl-l-piperidyl) ethyl chloride;

3p-ch-1oro-4-[3-(4-isopropyl-l-piperidyl)propoxy1-5-ethoxynitrobenzene using 2-chloro-4-nitro-6-ethoxyphenol and 3-(4-isopropy1-l-piperidyl) propyl chloride;

3-ch1oro-4- [2- (2,4,6-trimethyl-l-piperidyl)ethoxy] 5- methoxynitrobenzene using 2-chloro-4-nitro-6-methoxyphenol and 2-(2,4,6-trimethyl-l-piperidyl)ethyl ch1oride;

3-bromo-4- [2 (2,2,6-trimethyl-l-piperidyl) ethoxy] -6- methoxynitrobenzene using 2-brorno-4-nitro-5-methoxyphenol and 2-(2,2,6-trimethyl-1-piperidyl)ethyl chlo- 3-brorno-4-[3-( 2-butyl-1-pyrrolidyl)piopoxy1-5-propoxynitrobenzene using 2-bromo-4-nitro-6-propoxyphenol and 3-(Z-butyl-l-pyrrolidyl)propyl chloride; 3-chloro-4-[ 3- 2-sec-butyl-1-pyrrolidyl) propoxy] -5-butoxynitrobenzene using 2-chloro-4-nitro-6-butoxyphe- 1101 and 3-(Z-sec-butyl-d-pyrrolidyl)propyl chloride; 3-broino-4-[2-(2-isobutyl-l-pyrrolidyDethoxy]-5-methoxynitrobenzene using 2-bromo-4-nitro-6-rnethoxyphen01 and 2-(2-isobuty1-1-pyrrolidyl)ethyl chloride; 3-ch1oro-4- 2,4-dirnethyl-l-pyrrolidyl) ethoxy] -5-propoxynitrobenzene using Z-chloro-4-nitro-6-propoxyphe- 1101 and 2-(2,4-dimethyl-1-pyrrolidyl)ethyl chloride;

13-chloro-4-[3-(3,4-diethyl-1-pyrrolidyl) propoxy]-5-butoxynitrobenzene using 2-chloro-4-nitro--butoxyphenol land 3-(3,4-diethyl-l-pyrrolidyl)propyl chloride; 3 -bromo-4- [2- 3 -ethyl-2,4-dimethyll-pyrrolidyl) eth- 8 oxy]-5-hexoxynitrobenzene using 2-bromo-4-nitro-6 hexoxyphenol and 2-(3-ethyl-2,4-dimethyl-l-pyrrolidyl)ethyl chloride;

3 -chloro-4- [3 2-ethyl-3 ,4,5 -trimcthyll-pyrrolidyl) propoxy]-5-ethoxynitrobenzene using 2-chloro-4-nitro-6 ethoxyphenol and 3-(2-ethyl-3,4,5-trimethyl-l-pyrrolidyl)propyl chloride;

' 3-bromo-4- [2- 3 ethyl-2,4,5 -trirnethyl-1-pyrrolidyl) ethoxy]-5-methoxynitrobenzene using 2-bromo-4-nitro6- methoxyphenol and 2-(3-ethyl-2,4,S-trimethyl-1-pyrrolidyl)ethyl chloride;

3 -chloro-4- 3- (2,4-diethyl-3 5-dimethyl-1-pyrrolidyl)propoxy] -6-methoxynitrobenzene using 2-chloro-4-nitro-5- methoxyphenol and 3-(2,4-diethyl-3,5-dimethyl-l-pyrrolidyl)propyl chloride;

3-brorno-4-[2-(2,2,5,5-tetramethyl-1-pyrrolidyl)ethoxy]- 6-ethoxynitrobenzene using 2-bromo-4-nitro-5-ethoxyphenol and 2-(2,2,5,5-tetramethyl-l-pyrrolidyl)ethyl chloride;

3-ch1oro-4- 3-(2,5-dimethyl-2,5-diethyll-pyrrolidyl) propoxy]-5-butoxynitrobenzene using 2-chloro-4-nitro-6- butoxyphenol and 3-(2,5-dimethyl-2,5-diethyl-l-pyrro1idy1)propyl chloride; 1

3 -bromo-4- [2-( 2,5 -dimethyl-2, 5-dipropyl l-pyrrolidyl) ethoxy] -5-octoxynitrobenzene using 2-bromo-4-nitro-6- octoxyphenol and 2-(2,S-dimethyl-LS-diproPyl l-pyrorolidy1)ethyl chloride; and the like.

These basic esters can be isolated in free base form or in the form of their acid addition salts, preferably the hydrochlorides.

C. H alo-(Lower-A l kox y) [LOwer-Tertiary-A mi (Polycarbon-Lower-A lkoxy) -Anilines The preparation of these compounds is illustrated by the following preparation of 3-bromo-4-(2-diethylaminoethoxy)-S-n-propoxyaniline: A solution containing 4.1 g. of 3 brorno-4-(2-diethylarninoethoxy}S-n-propoxynitrobenzene monohydrochloride, 35 ml. of ethanol and 35 ml. of water was added slowly with stirring under an atmosphere of nitrogen to a refluxing mixture containing 3.3 g.

vof iron powder, 0.3 ml. of concentrated hydrochloric acid,

50 ml. of ethanol and 50 ml. of water. The reaction mixture was heated at reflux with stirring for an additional two hours. It was then made basic with sodium bicarbonate, the solid that separated was filtered, and the filtercake was Washed well with hot ethanol. The filtrate was evaporated to dryness in vacuo, the residue was dissolved in water, the resulting aqueous solution was made strongly basic with potassium hydroxide to liberate 3-brorno-4-(2- diethylaminoethoxy)-5-npropoxyaniline which was taken up in ether. The other solution was dried over anhydrous sodium sulfate, treated with decolorizing charcoal, and filtered. A slight excess of ethereal hydrogen chloride was added to the ether filtrate. The resulting precipitate was recrystallized from ethanol-ether to yield, as fine needles, the product, 3 brorno 4 (2 diethylaminoethoxy)-5-npropoxyaniline in the form of its dihydrochloride salt,

dure described by Hoppe et al. [1. Am. Pharm. Assoc. 39, p

147 (1950)] as modified by Luduena. and Hoppe [J. Pharm. & Exptl. Therap. 104, 40 (1952)], this compound was found to be only about four times as irritating as procaine hydrochloride.

Other halo-(lower-alkoxy}[lower-tertiary-amino(polycarbon-lower-alkoxy)]-anilines that can be prepared according to the foregoing procedure used for the preparation of 3-bromo-4-(2-diethylaminoethoxy)-5-n-propoxyaniline ,using the corresponding halo-(loweralkoxy)- [lower tertiary-amino(polycanbon-lower-alkoxy)]-nitrobenzene include:

3 -bromo-4-(2-dimethylaminoethoxy)-5-n-prop oxyaniline,

3 -chloro-4-(2-diethylaminoethoxy)-5-npropoxy aniline,

3 -bromo-'4-(2-di-n-butylaminoethoxy)-5 -n-prop oxyaniline,

3-bromo-4-(4-diethylaminobutoxy)-5 -n-propoxyaniline,

3 -bromo-4- [Z-(N-methyl-N-ethyl) aminoethoxy] -5-n-propoxyaniline,

3 -bromo-4-(3 -diethylamino -2-propoxy)-5 -n-prop oxyaniline,

3-bromo-4-(2 diethylaminoethoxy)-S-n-octoxyaniline,

2-(2-diethylaminoethoxy)-4-isopropoxy-S-bromoaniline,

2-(2-diethylamino ethoxy)-3 -bromo-5 -n butoxyaniline,

2-bromo4-n-propoxy-5- [3-( l-piperidyD-propoxy] aniline,

2-ethoxy-4 [2-(3-ethyl- 1-piperidyl)ethoxy] -5-chloroaniline,

2-chloro-4-methoxy-6- [3-( l-pyrrolidyDpropyl] aniline,

2- [2-(2,5-dimethyl-1 -pyrrolidyl)ethoxy] -4-methoxy-5- bromoaniline,

3 -io do-4-(2-diethylaminoethoxy)-5-npropoxy aniline,

3 -fiuoro-4-(2-diethylamino ethoxy)-5 -methoxyaniline,

3-chloro-4- [Z-(Z-methyl- 1 -piperidy1)ethoxy] -5-methoxyaniline,

3 -chlro -4- [3 (4-methyll -piperidyl) pro p oxy] --ethoxyaniline,

3-bromo-4- 2-(2,6-dimethyll-piperidyDethoxy] -6-ethoxyaniline,

3 -chloro-4- [2- (2 ethyl-3 -methyll-pi p eridyl)ethoxy] -5- prop oxyaniline,

2-bromo-4- 3-(2-ethyl-5-methyll-piperidyDpropoxy] -5 methoxyaniline,

3-chloro4- 3-(2-methyl-3-ethyll-piperidyl)propoxy] -5- ethoxyaniline,

3-chloro-4 2-(4-isopropyll-piperidyDethoxy] -6-methoxyaniline,

3-chloro-4- [2-(2 butyl-1-piperidyl)ethoxy] 5-methoxyaniline,

3 -bromo-4- [3-(3-butyl-1-piperidyl)propoxy] -5-ethoxyaniline,

3-bromo4- [2-(2-isobutyll-piperidyDethoxy] -5-methoxyaniline,

3-chloro-4- 3-(4-isopropyll piperidyl)propoxy] -5-ethoxyaniline,

3-chloro-4- [2-(2,4,6-trimethyll-piperidyl)ethoxy] -5-methoxyaniline,

3 -bromo-4- [2-(2, 2, 6-tr-imethyl-1-piperidyl)ethoxy] -6-methoxyaniline,

3 -brorno-4- 3-(3,4-diethyl-1-piperidyl)propoxy] -6-methoxyaniline,

3-chloro-4- [2-(2-methyll pyrrolidybethoxy] -5-methoxyaniline,

3-bron1o-4- 3-(3 -methyl-1-pyrrolidyl)propoxy] -5-ethoxyaniline,

3 -chloro-4- [2-(2-ethyll-pyrrolidyDethoxy] -6-methoxyaniline,

3- bromo-4- 3-(2-butyl-l -pyrrolidyl) prop oxy] -5-propoxyaniline,

3-chloro-4- [3 -(2-sec-butyll -pyrrolidyl)propoxy] -5- butoxyaniline,

3 -bromo-4- [Z-(Z-isobutyll -pyrrolidyl) ethoxy] -5 -rnethoxyaniline,

3-chloro-4- [2-(2,4-dimethyl-1pyrrolidyl)ethoxy] -5-propoxyaniline,

3-chloro-4- 3,4-diethyll-pyrrolidyl)propoxy] -5 but0xyaniline,

3-bromo-4- [2-(3-ethyl-2,4-dimethyll-pyrrolidyDethdxy] S-hexoxyaniline,

3-chloro-4- 3-(2-ethyl-3,4,5-trimethyl l-pyrrolidyDpropoxy] -5-ethoxyaniline,

- phenol.

A. 2-Br0m0-4-Nitro-6-Methoxyphenol In practicing our invention we prepared this compound 7 [Robertson, J. Chem. Soc. 93, 792 (1908)], by the procedure described in Example 1A for the preparation of the corresponding 2-bromo-4-nitro-6-npropoxyphenol using 33.8 g. of 2-methoxy-4-nitrophenoi, 300 m1. of acetic acid and 35.2 g. of bromine in 250 ml. of acetic acid. There was thus obtained 43.1 g. of 2-bromo-4-nitro-6-rnethoxyphenol, MP. 159.7-1-60.3 C. This same tri-substitutedphenol was obtained by the slow addition of 8.0 g. of bromine in ml. of methanol to 6.22 g. of the potassium salt of 2-methoxy-4-nitrophenol in ml. of water to yield 3.03 g. of product. 2-bromo-4-nitro-6-methoxyphenol was also obtained using pyridinium bromide perbromide as the brominating agent, as follows: To a solution containing 8.5 g. of 2-methoxy-4-nitropheno1 in 75 ml. of acetic acid and 0.6 ml. of 30% hydrogen bromide in acetic acid was added dropwise with stirring over a period of thirty minutes a hot solution containing 20.5 g. of pyridinium bromide perbrornide and 45.1 g. of fused sodium acetate in 200 ml. of acetic acid. Stirring was continued for an additional forty minutes and the reaction mixture was then poured with stirring into two liters of an ice-water mixture. The precipitated product was collected and recrystallized from ethanol-water.

Z-methoxyA-nitrophenol was prepared starting with 1,2-dimethoxybenzene following the procedure given in Example 1A for the preparation of 2-n-propoxy-4-nitro- Thus, 61.6 'g. of 1,=2-dimethoxy-4-nitrobenzene, M.P. 97.3-98.0" C.,. was obtained using 50 g. of 1,2-dimethoxybenzene in 50 ml. of acetic acid, 60 ml. of concentrated nitric acid and 100 m]. of water. Z-methoxy- 4-nitrophenol, M.P. l00100.5 C., was obtained in a yield of 3.9 g. using 5.0 g. of l,2-dimethoxyi-nitrobenzene, 10 g. of potassium hydroxide, 100 m1. of Water and a reflux period of about fifteen hours.

B. H a lo-Methoxy- [Lower-Tertiary-A m ino (Polycarb 0n- Lower-A lko-xy) ]-Nitr0benezenes The preparation of these compounds is illustrated by the preparation of 3-bromo-4-(Z-diethylaminoethoxy)-5 methoxynitrobenzene following the procedure given in Example 1B using 9.9 g. of 2-bromo-4-nitro6-methoxyphenol, 0.9 g. of sodium, 20 ml. of ethanol, 75 vml. of toluene and 5.4 g. of Z-diethylaminoethyl chloride in 75 ml. of toluene. There was thus obtained 8.24 g. of 3 bromo 4 (2 diethylaminoethoxy) 5 methoxynitrobenzene in the form of its monohydrochloride, M.P. 170.4-172.6 C. (corn).

Analysis.-Calcd. for C H BrN O .HCl: Cl-, 9.24; N 3.65. Found: (31 9.17; NT1,1

Other halo methoxy [lower tertiary amino (polycarbon-lower-alkoXy)]nitr0benzenes that can be prepared according to the above procedure used for the preparation of 3-bromo-4-(Z-diethyIaminoethoXy)-5-methoxy nitrobenzene using the appropriate halo-methoxy-nitrophenol and lower-tertiary-amino-(polycarbon-loWer-alk- 1 NT! stands for nitro nitrogen as determined bytitration tttiIith standard titanous chloride in glacial acetic acid soluyl) halide include: 3-bromo-4-[3-(l-piperidyl)propoxy]- S-methoxynitrobenzene using 2-bromo-4-nitro-6-methoxy phenol and 3-(1-piperidyl)propyl chloride; 2-(2-diethylaminoethoxy) 3 methoxy 5 bromonitrobenzene using 2-methoxy-4-bromo-6-nitrophenol [Robertson, J. Chem. Soc. 93, 791 (1908)] and Z-diethylaminoethyl bromide; 2 bromo 3 (2 diethylaminoethoxy) 4- methoxynitrobenzene 'using 2-bromo-3-nitro-6-methoxyphenol [Jones and Robinson, J. Chem. Soc. 111, 917 (1916)], and Z-diethylaminoethyl chloride; 2-bromo-4- methoxy 5 (2 diethylaminoethoxy)nitrobenzene using 2-methoxy-4-bromo-5-nitrophenol [Raiford and Silker, J. Org. Chem. 2, 346 (1937)], and Z-diethylaminoethyl chloride; 2 [2 (1 pyrrolidyl)ethoxy] 3 chloro 6- methoxynitrobenzene using 2-nirto-3-rnethoxy-6-chlorophenol [Meldola and Eyre, 1. Chem. Soc. 81, 999 (1902)] and 2-(l-pyrrolidyl)ethyl chloride; 2-methoxy-4-chloro- 6-(2-diethylaminoethoxy)nitrobenzene using 2-nitro-3- methoxy-S-chlorophenol (Hodgson and Batty, J. Chem. Soc. 1934, 1433) and 2-diethylaminoethyl chloride; 2- chloro 4 rnethoxy 6 (2 diethylaminoethoxy)nitrobenzene using 2-nitro-3-chloro-5-methoxyphenol (Hodgson and Wignall, J. Chem. Soc. 1928, 329) and 2-diethylaminoethyl chloride; 2-(2-diethylaminoethoxy)-4-methoxy-S-bromonitrobenzene using 2-nitro-4-bromo-5-rnethoxyphenol (Hodgson and Dyson, J. Chem. Soc. 1935, 946) and Z-diethylaminoethyl chloride; 2-(2-diethylarninoethoxy)-4-methoxy-S-chloronitrobenzene using 2-nitro-4- chloro-S-methoxyphenol [Beilstein, 6 (404)] and 2-diethylarninoethyl chloride; 2-methoxy-4-bromo-5-(Z-diethylaminoethoxy)nitrobenzene using 2-bromo-4-methoxy- S-nitrophenol and Z-diethylaminoethyl chloride; 2-(2-diethylaminoethoxy) 4-methoxy 5 iodonitrobenzene using 2-nitro-4-iodo-5-methoxyphenol [Stephens, J. Chem. Soc. 87, 1201 (1905)] and Z-diethylaminoethyl chloride; 2 (2 diethylaminoethoxy) 3 iodo 6 methoxynitrobenzene using 2-nitro-3 -methoxy-6-iod0phenol [Meld- 01a and Hay, J. Chem. Soc. 91, 1484 (1907)] and 2-diethylarninoethyl chloride; and the like.

C. Halo-Methoxy-[Lower-Tertiary-A min(Polycarb0n- Lower-A lkoxy) ]-A nilines The preparation of these compounds is illustrated by the preperation of 3-bromo-4-(Z-diethylaminoethoxy)-5- methoxyaniline following the procedure given in Example 1C using 23.0 g. of 3-bromo-4-(Z-diethylaminoethoxy)--methoxynitrobenzene hydrochloride, 420 ml. of a mixture containing equal parts of ethanol and water, 19.9 g. of iron powder and 1.5 ml. of hydrochloric acid in 600 ml. of a 1:1 ethanol-water mixture. There was thus obtained 23.3 g. of 3-bromo-4-(2-diethylaminoethoxy)- S-methoxyaniline in the form of its dihydrochloride, M.P. 175180 C. Since this dihydrochloride was found in an earlier experiment to lose part of an equivalent of hydrogen chloride on drying, it was converted into the monohydrochloride by first converting more than half of the dihydrochloride salt to the free base by treating its aqueous solution with alkali and extracting the basic ether with ether or ethyl acetate, and adding the remaining dihydrochloride salt in absolute ethanol solution. The precipitated mono-salt Was collected and recrystallized from ethanol-ether to yield 15.4 g. of 3-bromo-4-(2-diethylcarbon-lower-alkoxy)l-anilines that can be prepared according to the foregoing procedure used for the prepararation of 3-bromo-4-(Z-diethylaminoethoxy)-5-methoxyaniline using the corresponding halo-methoxy-[lowertertiary amino(polycarbon lower alkoXYH nitrobenzene include:

3-bromo-4- [3-( 1-piperidyl)propoxy] -5-methoxyaniline, 2- Z-diethylarninoethoxy -3 -rnethoxy-5-bromoaniline, 2-bromo-3 (Z-diethylaminoethoxy -4-methoxyaniline, 2-bromo-4-methoxy-5- Z-diethylaminoethoxy) aniline, 2- [2-( 1-pyrrolidyl)ethoxy] -3-chloro 6-methoxyaniline, 2-methoxy-4-chloro-6- Z-diethylarrinoethoxy) aniline, 2-chloro-4-rnethoxy 6- Z-diethylaminoethoxy) aniline, 2- Z-diethylaminoethoxy) -4-methoxy-5 -bromoaniline, 2-( Z-diethylaminoethoxy) -4-rnethoxy-5 -chloroaniline, 2-methoxy-4-bromo-5-( Z-diethylamino ethoxy) aniline, 2- Z-diethylaminoethoxy -4-methoxy-5 -iodoaniline,

2- (Z-diethylaminoethoxy) -3-iodo-6-methoxyaniline,

and the like. These basic ethers can be isolated in free base form or in the form of their acid addition salts, preferably the monohydrochlorides.

EMMPLE 3 A. 2-Brom0-4-Nitr0-6-Eth0xyphenol This compound was prepared following the procedure described in Example 1A for the preparation of the corresponding Z-bromo-4-nitro-G-n-propoxyphenol using 36.6 g. of 2-ethoxy-4-nitrophenol, 250 ml. of acetic acid and 35.2 g. of bromine in ml. of acetic acid. There was thus obtained 39.5 g. of 2-bromo-4-nitro-6-ethoxyphenol, M.P. l60.2l61.8 C. (corn).

Analysis.Caicd. for C H BrNO N, 5.34; Br, 30.50. Found: N, 5.32; Br, 30.85.

2-ethoxy-4-nitrophenol was prepared starting with catechol following the procedure given in Example 1A for the preparation of 2-n-propoxy-4-nitrophenol. 1,2-diethoxybenzene was prepared as follows: To a solution of 220.2 g. of catechol, 171.5 g. of sodium hydroxide and one liter of water was added slowly under nitrogen with rapid stirring at about 10 C. 524 ml. of diethyl sulfate.

The resulting suspension was allowed to warm up to room temperature, taking about four hours, and was then heated to about 7080 C. for an additional two and onehalf hours. The mixture was steam distilled, the distillate chilled and the precipitate collected. The precipitate was recrystallized from methanol-water, yielding 207.1 g. of 1,2-diethoxybenzene, M.P. 41.3-42.1 C. A yield of 240.1 g. of 1,2-diethoxy-4-nitrobenzene, M.P. 72.073.4 C., was obtained using 199.5 g. of 1,2-diethoxybenzene in 400 ml. of acetic acid and ml. of concentrated nitric acid in a mixture of 330 ml. of water and 250 ml. of acetic acid. 2-ethoxy-4-nitrophenol, M.P. 95.5-97.5 C., was obtained in a yield of 50.5 g. using 63.3 g. of l,2-diethoxy-4-nitrobenzene, 127 g. of potassium hydroxide, 800 m1. of water, 800 ml. of ethylene glycol monomethyl ether and a reflux period of about three days.

B. 3-Br0m0-4-(Z-Diethylaminoetkoxy) -5-Eth0xy- N itrobenzene The preparation of this compound was carried out following the procedure given in Example 1B using 13.1 g. of 2-bromo-4-nitro-6-ethoxyphenol, 1.2 g. of sodium, 25 ml. of ethanol, 75 ml. of toluene and 6.8 g. of 2-diethylaminoethyl chloride in 70 ml. of toluene. There was thus obtained 15.8 g. of 3-bromo-4-(Z-diethylaminoethoxy)-5-ethoxynitrobenzene in the form of its monohydro chloride, M.P. l67.0168.2 C. (corn).

Analysis.Calcd. for C H BrN O HCl: Cl, 8.92; N- 3.53. Found: Cl-, 8.90; NTis 3.32.

C. 3 -Brom0-4 -(2 -Dierhy laminoethoxy -5 -Ezh0xyaniline This preparation was carried out following the procedure described in Example 1C using 23.9 g. of 3-bromo4- (Z-diethylaminoethoxy)-5-ethoxynitrobenzene hydrochloride, 420 ml. of a mixture containing equal parts of ethanol and water, 19.9 g. of iron powder and 1.5 ml. of hydrochloric acid in 600 ml. of a 1:1 ethanol-water mixture. There was thus obtained 22.3 g. of 3-bromo-4-(2-diethylaminoethoxy)-5-ethoxyaniline in the form of its dihydrochloride salt, M.P. 148-168 C. The dihydrochloride was converted as above into 16.0 g. of the corresponding monolaydrochloride salt, M.P. 169.0-173.4 C. (corn).

Analysis.Calcd. for C14H23B1'N202-HC11 C, H, 6.58; Cl, 9.64. Found: C, 45.43; H, 6.58; Cl, 9.78.

Pharmacological evaluation of 3-bromo-4-(2-diethylminoethoxy)--ethoxyaniline dihydrochloride according to the procedures referred to in Example has shown that this compound (in terms of its base) is approximately six times as active at local anesthetic as procaine hydrochloride and is about four times as irritating.

3 bromo 4 (2 diethylaminoethoxy) 5 ethoxyaniline can be reacted with hydrobromic acid, hydriodic acid, nitric acid, phosphoric acid, sulfamic acid, sulfuric acid, acetic acid, citric acid, tartaric acid, lactic acid, quinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid to give the hydrobromide, hydriodide, nitrate, phosphate or acid phosphate, sulfamate, sulfate or acid sulfate, acetate, citrate or acid citrate, tartrate or acid tartrate, lactate, quinate, methanesulfonate, ethanesulfonate, benzenesulfonate and p-toluenesuifonate salts, respectively.

3 bromo 4 (2 diethylaminoethoxy) 5 ethoxyaniline in the form of its hydrogen cyanide salt can be con verted to the hydrochloride salt by passing an aqueous alcoholic solution of the former over anion-exchange resin saturated with chloride ions, for example, Rohm and Haas Amberlite IRA-400 resin.

EXAMPLE 4 A. 2-Br0m0-4-Nitr0-6-n-But0xyphenol This compound was prepared following the procedure described in Example 1A for the preparation of the corresponding 2-bromo-4-nitro-6-n-propoxyphenol using 8.8 g. of 2-n-butoxy-4-nitrophenol, 80 ml. of acetic acid and 7.4 g. of bromine in 90 ml. of acetic acid. There was thus obtained 5.9 g. of 2-bromo-4-nitro-6-n-butoxypl1eno1, M.P. 97.2-98.4 C. (corn).

Analysis.Calcd. for C H BrNO N, 4.83; Br, 27.53. Found: N, 4.87; Br, 27.38.

2-n-butoxy-4-nitrophenol was prepared starting with catechol following the procedure given in Example 1A for the preparation of Z-n-propoxy-4-nitrophenol. 1,2-din-butoxybenzene, B.P. 149-152 C. at 16 mm., was prepared using 154.2 g. (one portion) of n-butyl benzenesulfonate, 39.6 g. of catechol, 46.9 g. of potassium hydroxide, 270 ml. of ethanol, 90 ml. of water and an extra 5.0 g. portion of potassium hydroxide; the yield was 50.1 g. 1,2-di-n-butoxy-4-nitrobenzene, M.P. 51.5-53.0 C., was obtained in a yield of 58.0 g. using 50.1'g. of 1,2-di-nbutoxybenzene in 65 ml. of acetic acid and 30.1 ml. of concentrated nitric acid in 115ml. of acetic acid. 2-11- butoxy-4-nitrophenol, M.P. 38-39 C., was obtained in a yield of 9.0 g. using 13.1 g. of'1,2-di-n-but0xy-4-nitrobenzene, 26 g. or" potassium hydroxide, 260 ml. of water, 260 ml. of ethylene glycol monomethyl ether and a reflux period of about four days.

B. 3 -Br0m0'-4- (Z-Dz'ethylaminoefhoxy -5 -n-Bllf0xy- N itrobenz ene This preparation was carried out following the procedure given in Example 13 using 14.5 g. of 2-bromo-4- nitro-6-n-butoxyphenol, 1.2 g. of sodium, 50 ml. of ethanol, 100 ml. of toluene and 6.8 g. of 2-diethylaminoethyl chloride in 140 ml. of toluene. There was thus obtained 15.4 g. of 3-bromo-4-(2-diethylaminoethoxy)-5-n-butoxynitrobenzene in the form of its monohydrochloride, M.P. 982-1000 C. (corn).

Analysis.Calcd. for C H BrN O l-ICl: N, 6.58; Cl 0.33. Found: N, 6.84; Cl, 8.24.

i4 C. 3-Br0m0-4 -(Z-Diethylamincrethoxy)-5-n-But0xy aniline This preparation was carried out following the procedure described in Example 10 using 5.5 g. of 3-br-omo- 4-(2-diethylaminoethoxy)-5-n butoxynitrobenzene hydrochloride, ml. of a 1:1 mixture of ethanol-water, 4.4 g. of iron powder and 0.4 ml. of hydrochloric acid in ml. of a 1:1 mixture of ethanol-waten There resulted a yield of 5.0 g. of 3-bromo-4-(Z-diethylaminoethoxy)-5- nbutoxyaniline in the storm of its dihydrochloride salt, M.P. 171.0-190.6C. (COIL).

AnaZysis.-Calcd. for c l-l BrN O ll-lCl: C, 44.46; H, 6.77; 01", 16.41. Found: C, 44.61; H, 6.88; 01-, 16.2 9.

Pharmacological evaluation of 3-bromc-4-(2-diethylaminoethoxy)-5-n-butoxyaniline dihydrochloride according to the procedures referred to in Example 10 has shown that this compound (in terms of its base) is approximately twenty-two times was active a local anesthetic as procaine hydrochloride and is about nine as. irritating.

EXAMPLE 5 A. 2-Br0m -4-Nitr0'-6-n-Hex0xyphen0l This compound was prepared following the procedure described in Example 2A for the preparation of the corresponding 2-bromo-4-nitro-6-methoxyphenol using 2.2 g. 'ofthe potassium salt of 2-n-hexoxy-4-nitrophenol in 45 ml. of acetic acid, and a mixture of 3.27 g. of pyridinium bromide perbromide and 0.2 ml. of 30% HBr in acetic acid in 45 ml. of acetic acid. There was thus obtained 1.79 g. of 2-bromo-4-nitro-6-n-hexoxyphenol, M.P. 84.2- 88.2 C. (corn).

Analysis.-Oalcd. for C H BrNOy N, 4.40; Br, 25.12. Found: N, 4.37; Br, 24.90.

2-n-hexoxy-4-nitrophenol was prepared starting with catechol following the procedure given in Example 1A for the preparation of 2-n-propoxy-4 nitrophenol. .1,2-din-hexoxybenzene, B.P. 182-185 C. at 10 mm, was obtained [in a yield of 33.8 g. using 116.3 g. (one portion) of n-hexyl benzenesulfonate, 22.0 g. of catechol, 26.1 g. of potassium hydroxide, ml. of ethanol, 50 ml. of water and an extra 9.8 g. portion of potassium hydroxide. A yield of 39.4 g. of 1,2-di-n-hexoxy-4-nitrobenzene, M.P. 48-50 C., was obtained using 36.1 g. of 1,2-di-nhexoxybenzene in 40 ml. of acetic acid and 17.3 ml. of concentrated nitric acid in 65 of acetic acid. 2-n 11exoxy-4-nitrophenol was obtained as a red-brown oil using 5.0 g. of 1,2-di-n-hexoxy-4-nitrobenzene, 25 g. of potassium hydroxide, 100 ml. of water, 100 ml. of ethylene glycol monomethyl other land a reflux period of over five days; the yield was 2.73 g. of product.

B. 3-Br0 m0-4 Z-Diethylaminoethoxy -5-n-Hex0xynitrobenzene This preparation was carried out following the procedure given in Example 1B using 8.0 g. of 2-bromo-4- nitro-6-n-hexoxyphenol, 0.6 g. of sodium, 40 ml. of ethanol, 100 ml. of toluene and 3.4 g. of Z-diethylaminoethyl chloride in 2 0 ml. of toluene. The yieldwas 8.2 got 3 bromo-4-(Z-diethylaminoe-thoxy)-5-n-hexoxynitrobenzene in the .form of its monohydrochloride, M.P. 127.6- 129.0 C. (corn).

Analysis.-Calcd. for C H BrN O l-ICl: N 3.09; CI-, 7.83. Found: N 3.04; Cl, 7.76.

Following the above procedure using an equivalent quantity of 2-'bromo4-nitro-6-n-amoxyphenol or 2-bromo- 4-nitro-6-isoamoxyphenolin place or 2-brom0-4-nitro-6- n-hexoxyphenol, there is obtained in the form of the monohydrochloride salt 3-bromo-4-(Z-diethylaminoethoxy)-5- n-amoxynitrobenzene or 3-bromo-4-(Z-diethylaminoethoxy)-5-isoamoxynitrobenzene, respectively.

C. 3-Br0m0-4-(2-Diethylaminoethoxy -5-n-Hex0xyaniline This preparation was carried out following the procedure described in Example 1C using 6.1 g. of 3-br0mo- 4-(2-diethylaminoethoxy)-5-n-hexoxynitrobenzene hydrochloride, 95 ml. of a 1:1 mixture of ethanol-water, 4.6 g. of iron powder and 0.4 ml. of hydrochloric acid in 135 ml. of a 1:1 ethanol-water mixture. There was thus obtained 5.0 g. of 3-bromo-4-(Z-diethylaminoethoxy)-5-nhexoxyan-iline in the form of its dihydrochloride salt, M.P. 1930-1960 C. (corn).

Analysis.--Calcd. tor C H BrN O lHc-l: C, 46.97; H, 7.21; 01-, 15.41. Found: C, 47.13; H, 7.56; 01-, 15.36.

Pharmacological evaluation of 3-bromo-4-(2-diethylaminoethoxy)-5-n-hexoxyaniline dihydrochloride according to the procedure referred to in Example 1C has shown that this compound (in terms of its base) is approximately thirty-nine times as active a local anesthetic as procaine hydrochloride.

Following the above procedure using 3-bromo-4-(2- diethylaminoethoxy)-5-n-arnoxynitrobenzene hydrochloride or 3-bromo-4-(Z-diethylaminoethoxy)-5-isoamoxynitro-benzene hydrochloride, there is obtained in the form of the dihydrochloride 3-bromo-4-(Z-diethylaminoethoxy) S-n-amoxyaniline or 3-bromo-4-(Z-diethylarninoethoxy) -5-isoamoxyaniline, respectively.

EXAMPLE 6 A. 2-Br0m0-4-Nitr0-6-Benzyloxyphenol This compound was prepared following the procedure described in Example 2A for the preparation of the corresponding 2-bromo-4-nitro-6-methoxyphenol using 24.5 g. of 2-benzyloxy-4-nitrophenol, 3 ml. of 30% HBr in acetic acid, 40.9 g. of pyridinium bromide perbromide, 8.2g. of fused sodium acetate and 700 ml. of acetic acid. There was thus obtained 20.2 g. of 2-bron1o-4-nitro-6- benzyloxyphenol, M.P. 126.0-1344" C. (corn).

Analysis.Calcd. for C H 'BrNO N, 4.32; Br, 24.66. Found: N, 4.04; Br, 24.95.

24benzyloxy-4-nitrophenol was prepared starting with catechol using the procedure given in Example 1A for the preparation of Z-mpropoxy-4-nitrophenol. 1,2-dibenzyloxy-benzene was prepared as follows: A mixture containing 278.2 g. of benzyl chloride, 110.1 g. of catechol, 148.5 g. of sodium carbonate, 166g. of potassium iodide, 8 ml. of water (used to dissolve the potassium iodide), and 900 ml. of ethanol was stirred at reflux under an atmosphere of nitrogen for about twelve hours. The warm suspension was filtered and the filter cake washed well with hot absolute ethanol. The combined filtrates were evaporated to a volume of about 400 ml., chilled and the precipitate that separated was collected and recrystallized from etha- 1101 to yield 130.3 g. of 1,2-dibenzyloxybenzenc, M.P. 58- 59 C. 1,Z-dibenzyloxy-4-nitrobenzene, M.P. 98.8- 99.5" C., was obtained using 116.1 g. of 1,2-dibenzyloxybenzene in 600 ml. of acetic acid and 53.4 of concentrated nitric acid in 650 ml. of acetic acid; the yield was 124.6 g. 2-benzyloxy-4-nitrophenol, M.P. 80.282.0 C., was obtained in a yield of 42.9 g. using 100.6 g. of 1,2- dibenzyloxy-4-nitrobenzene, 201 g. of potassium hydroxide, 1800 ml. of water, 1800 ml. of ethylene glycol monomethyl ether and a reflux period of about forty hours.

B. 3-Br0m04-(Z-Diethylaminoethoxy -5-Benzyl0xynitrobenzene This preparation was carried out following the procedure given in Example 1B using 16.2 g. of 2-bromo-4- nitro6-benzyloxyphenol, 1.2 g. of sodium, 50 ml..of ethanol, 100 ml. of toluene and 6.8 g. of Z-diethylamino- 1 6 C. 3-Br0m 0-4 (Z-Diez'hylami noethoay -5 -Benzy loxy- A niline This preparation was carried out following the procedure described in Example 1C using 4.6 g. of S-bromo- 4 (Z-diethylaminoethoxy)-5-benzyloxynitrobenzene hydrochloride, 70 ml. of a 1:1 mixture of ethanol-water, 3.3 g. of iron powder and 0.30 ml. of hydrochloric acid in ml. of a 1:1 mixture of ethanol-water. There was thus obtained 4.0 g. of 3-bromo-4-(2-diethylamino ethoxy)-5-benzyloxyaniline in the form of its dihydro chloride salt, M.P. 2232-2246 C. (corn).

' Analysis.-Calcd. for C H BrN O 2HCl: C, 48.94; H, 5.84; Cl, 15.21. Found: C, 49.04; H, 5.92; C1-, 15.11.

Pharmacological evaluation of 3-bromo-4-(2-diethylaminoethoxy) 5 benzyloxyaniline dihydrochloride according to the procedure referred to in Example 1C has shown that this compound (in terms of its base) is approximately'nine times as active a localanesthetic as procaine hydrochloride and is about eleven times as irritating.

EXAMPLE 7 A. 2-Chloro-4-Nitro-6-Methoxypl1enol A mixture containing 12.6 g. of 2-methoxy-4-nitrophenol and 65 m1. of sulfuryl chloride was refluxed for three hours under anhydrous conditions. The excess sulfuryl chloride was decomposed by cautious addition of ethanol and the resulting solution was added to water. The solid that separated was collected and recrystallized from ethanol-water to yield a crystalline material melting over a wide range, indicating incomplete chlorination. The crystalline material was dissolved in ml. of chloroform; 65 ml. of sulfuryl chloride was added; and the mixture was refluxed four hours. The reaction mixture was concentrated by distillation to a volume of about 150 ml. and an equal volume of hot water was added. The resulting precipitate was collected, and recrystallized once from ethanol-water and once from isopropanol to yield 3.02 g. of tan crystalline product, 2-chloro-4-nitr0- 6-methoxyphenol, M.P. 146-1489 C.

Analysis.Calcd. for C H ClNO Cl, 17.43. Found: Cl, 16.90.

Alternatively the chloro-nitro-(lower-alkoxy)phenols can be prepared by the following procedure illustrated by the synthesis of 2-chloro-4-nitro-6-methoxyphenol: A solution of 7.67 g. (0.045 mole) of 2-methoxy-4-nitrophenol in 75 ml. of glacial acetic acid contained in a 250 m1. three-necked flask fitted with an air-condenser,

internal thermometer and gas inlet tube was treated with chlorine gas while maintaining the temperature below 35 C. Chlorine was passed through the solution for two hours, and the solution was then poured into one liter of ice water. The solid that separated was collected, dried and recrystallized from an ethanol-water mixture giving 5.13 g. of 2-chloro-4-nitro-6-methoxyphenol, M.P. 149.5l55.0 C. (unc0rr.).

B. 3 -Chlor0-4 (Z-Diethylaminoeth oxy -5 -M ethoxy- N itrobenzene This preparation was carried out following the procedure given in Example 1B using 20.4 g. of 2-chloro- 4-nitro-6-methoxyphenol, 2.3 g. of sodium, 50 ml. of ethanol, ml. of toluene and 13.5 g. of Z-diethylaminoethyl chloride. There was thus obtained 15.3 g. of 3-chloro-4-(Z-diethylaminoethoxy)-5 methoxynitrobenzene in the form of its monohydrochloride salt, M.P. 170.4171.8 C. (corn).

Analysis.Calcd. for C H ClN O HCl: Cl-, 10.46;

N'ri, 4.13. Found: Cl, 10.32; N 4.05.

C. 3-Chlor0-4-(Z-Diethylaminoethoxy)-5-Meth0xyaniline This preparation was carried out following the pro cedure described in Example 10 using 8.5 g. of 3-chloro- 4-(2-diethylaminoethoxy) methoxynitrobenze ne hydrochloride, 200 ml. of a 1:1 mixture of ethanol-water, 4.2 g. of iron powder and 0.5 ml. of hydrochloric acid in 250 ml. of a 1:1 mixture of ethanol-water. Ther was thus obtained 4.3 g. of 3-chloro-4-(2-diethylaminoethoxy)-5-methoxyaniline in the form of its monohydrochloride salt, M.P. 191.8-195.6 C. (corn).

Analysis.-Calcd. for C H ClN O HC1: C, 50.49; H, 7.17; CI, 11.48. Found: C, 50.50; H, 7.34; Cl-, 11.42.

Pharmacological evalution of 3-chloro-4-(2-diethylaminoethoxy)-5-methoxyaniline hydrochloride according to the procedures referred to in Example 1C has shown that this compound in terms of its base is about four times as active a local anesthetic as procaine hydrochloride and is about one and a half times as irritating.

EXAMPLE 8 A. 3-Chl0r0-4-(Z-Dimethylaminoethoxy)-5-Meth0xy- N itrobenzene B. 3-Clzl0r0-4-(Z-Dimethylaminoethoxy)-5-Meth0xy- Aniline This preparation was carried out following the procedure given in Example 1C using 15.56 g. of 3-chloro- 4-(Z-dimethylaminoethoxy) 5 methoxynitrobenzene in 250 ml. of a 1:1 mixture of ethanol-water, 16.7 g. of iron powder and 1 ml. of hydrochloric acid in 500 ml. of a 1:1 mixture of ethanol-water. There wasthus obtained 10.3 g. of 3-chloro-4-(Z-dimethylaminoethoxy)- S-methoxyaniline as its monohydrochloride salt, M.P. 162.0164.2 C. (corn).

Analysis.-Calcd. for C H CIN O HCI: Cl-, 12.61; C, 46.98; H, 6.10. Found: 01-, 12.65; C, 47.12; H, 6.21.

Pharmacological evaluation of 3-chloro-4-(2-dimethylaminoethoxy)-5-methoxyaniline according to the procedures referred to in Example 1C has shown that this compound in terms of its base is approximately two and one-half times as active a local anesthetic as procaine hydrochloride and about equally irritating.

EXAMPLE 9 A. 3-Chl0r0-4-(3-Dimethylaminopropoxy)-5- M ethoxynitrobenzene This preparation was carried out following the procedure given in Example 113 using 20.4 g. of 2-chloro-4- B. 3-Chl0r0-4-(S-Dimethylaminopropoxy)-5- M ethoxyaniline This preparation was carried out following the procedure described in Example 10 using 16.3 g. of 3-chloro 4-(3-dl11'16thY13rH1iHOPI'OPOXY)-5 methoxynitrobenzene in 250 ml. of a 1:1 mixture of ethanol-water, 16.8 g. of iron powder and 1 ml. of hydrochloric acid in 500 ml. of a 1:1 mixture of ethanol-water. There was thus obtained 10.1 g. of 3-chloro-4-(B-dimethylaminopropoxy)-5-meth- EXAMPLE 10 This preparation was oarried out following the procedure given in Example 13 using 20.4 g. of 2-chloro-4- nitro-o-methoxyphenol, 2.3 'g. of sodium in 50 ml. of ethanol, ml. of toluene, and 16.5 g. of 3-die-thylaminopropyl ohloride in 40 ml. of toluene. There was thus obtained 29.2 g. of 3-ch1-oro-4-(3-dtiethylaminopropoxy)-5-methoxynitrobenzene as its monohydrochloride salt, M.P. 162.8-164.4 C. (corn).

Analysis.-Calcd. for C H CIN O HCI: Cl", N 3.97. Found: C11 9.88; N 3.94.

B. 3-Chlor0-4-(3-Diethylaminopr0p0xy)-5- M ethoxyaniline This preparation was carried out following the procedure described in Example 1C using 28.3 g. of 3-chloro- 4-(3-diethylaminopropoxy) 5 methoxynitrobenzene hydroohloride in 400 ml. of a 1:1 mixture of ethanol-water, 26.8 g. of iron powder and 1.6 ml. of hydrochloric acid in 800 ml. of a 1:1 mixture of ethanol-water. There was thus obtained 15.3 g. of 3-ohloro-4-(3-diethylarninopropoxy)-5-methoxyaniline as its monohydrochloride salt, M.P. 135.0-137.6 C. (corn).

. Analysis-Calcd. for C H ClN O .HCl: 01*, 10.97;

C, 52.01; H, 7.48. Found: Cl, 11.01; C, 51.74; H, 7.50.

Pharmacological evaluation of 3-chloro-4-(3-diethylaminopropoxy)-5-rnetlroxyaniline hydrochloride according to the procedures referred to in Example 1C has shown that this compound in terms of its base is about five and one-half times as active a local anesthetic as procaine hydrochloride and about five times as irritating.

EXAMPLE 11 A. 3-Chl0r0-4- [2- (Z-Methyl-I-Piperidyl) Ethoxy] -5- M ethoxynitrobenzene This preparation was carried out following the procedure given in Example 13 using 30.5 g. of 2 chloro-4- nitro-6-methoxyphenol in 275 ml. of toluene, 3.45 g. of sodium in 75 ml. of ethanol and 24.3 g. of 2-(2-methyl-1- piperidyDethyl chloride in 50 ml. of toluene. There was thus obtained 39.7 g. of 3-chloro-4-[2-(Z-methyl-l-piperidyl)ethoxy]-5-rnethoxynitrobenzene as its monohydroo'hloride salt, M.P. 170.4171.4 C. (corn).

Analysis.-Calcd. for C H ClN O HCl: Cl", 9.71; N 3.84. Found: Cl, 9.65; N 3.85.

B. 3-Chl0r0-4-[2-(Z-Methyl-l-Piperidyl)Erhoxy1-5- Methoxyaniline This preparation was carried out following the procedure described in Example 1C using 18.3 g. of 3-chloro- 4-[2-'(Z-methyl-l-pipefiidyDethoxy]- 5 methoxynitrobenzene hydrochloride in 250 ml. of a 1:1 mixture of ethanol-water, 16.8 g. of iron powder and 1 of hydrochloric acid in 500 of a 1:1 mixture of ethanol-water. There was thus obtained 10.9 g. of 3-chloro-4-[2-(2- methyl-l-piperidyhethoxy] -5-methoxyaniline as its monohydrochloride salt, M.P. 208.8-2l6.2 C. (oorr.).

Analysis.-Calcd. for C H ClN O HCl: Cl", 10.58; C, 53.73; H, 7.22. 'Found: Cl-, 10.59; C, 54.00; H, 7.12.

Pharmacological evaluation of 3 chloro-4-[2-(2-methyl-1-piperidyl)ethoxy] 5 methoxyaniline hydrochloride according to the procedures referred .to in Example 1C has shown that this compound in terms of its free base is about six times as active a local anesthetic as procaine hydrochloride and about four times as irritating.

EXAMPLE 12 A. 3-Chlor0-4- [3- (2-M ethyl-1 -Piperidyl Propoxy] -5 M ethoxynitrobenzene This preparation was carried out following the procedure given in Example 13 using 40.7 g. of 2-chloro-4- piperidyl)propoxy]-5-methoxynitrobenzene as its monohydrochloride salt, M.P. 153.2-156.4 C. (corn).

Analysis.Calcd. for C H ClN O .HCl: Cl, 9.36;

N'r 3.70. Found: C1, N 3.70.

B. 3-Chlor0-4-[3(2-Methyl-1-Piperidyl)Pr0p0xy] 5-Methoxyaniline This preparation was carried out following the procedure described in Example 1C using 37.9 g. of 3-chlor 4 [3 (2 methyl 1 piperidyl)propoxy] methoxynitrobenzene hydrochloride in 500 ml. of a 1:1 mixture of ethanol-water,'33.5 g. of iron powder and 2 ml. of hydrochloric acid in one liter of a 1:1 mixture of ethanol-water. There was thus obtained 21.6 g. of 3-chloro- 4 [3 -(2 methyl 1 piperidyl)propoxy] 5 methoxyaniline as its monohydrochloride salt, M.P. 169.2- 172.4 C. '(corr.).

Analysis.-Calcd. for C H ClN O HCl: 01-, 10.15; C, 55.01; H, 7.50. Found: Cl, 10.00; C, 54.92; H, 7.67.

Pharmacological evaluation of 3-chloro-4-[3-(2-methyl-l-piperidyl)propoxyl-S-methoxyaniline hydrochloride according to the procedures referred to in Example 1C has shown that this compound in terms of its base is approximately six to eight times as active a local anesthetic as procaine hydrochloride and about four times as irritatmg.

EXAMPLE 13 A. 2-Ckl0ro-4-Nitr0-6-Ethoxyphenol This preparation was carried out using the procedure described in Example 7A using 36.6 g. of 2-ethoxy-4- nitrophenol, chlorine gas and 340 ml. of glacial acetic acid. There Was thus obtaned 34.2 g. of 2-chloro-4-nitro- 6-ethoxyphenol, 154.4158.5 C. (uncorn).

B. 3-Chl0ro-4-(Z-Diethylaminoethoxy)-5- Ethoxynitrobenzene This preparation was carried out following the procedure given in Example 1B using 32.6 g. of 2-ch1oro-4- nitro-6-ethoxyphenol, 3.5 g. of sodium in 50 ml. of ethanol, 270 ml. of toluene and 20.4 g. of Z-diethylaminoethyl chloride. There was thus obtained 44.5 g. of 3-chloro-4- (2 diethylaminoethoxy) 5 ethoxynitrobenzene hydrochloride, M.P. 170.0-174.4 C. (corn).

Analysis.--Calcd. for C 'H ClN O HCl: Cl, 10.03; N- 3.97. Found: Cl, 10.10; N 3.94.

C. 3-Chloro-4-(2-Diethylaminoethoxy -5 Ethoxyaniline This preparation was carried out following the procedure described in Example 1C using 17.7 g. of 3-chloro- 4 (2 diethy-laminoethoxy)-5-cthoxynitrobenzene hydrochloride in 250 m1. of a 1:1 mixture of ethanol-water, 16.8 g. of iron powder and 1 ml. of hydrochloric acid in 500 ml. of a 1:1 mixture of ethanol-water. There was thus obtained 13.2 g. of 3-chloro-4-(Z-diethylaminoethoxy)-5-ethoxyaniline as its monohydrochloride salt, M.P. 178.2-l80.8 C. (corn).

Analysis.-Calcd. for C H ClN O HC1: Cl, 10.97; C, 52.01; H, 7.48. Found: 01-, 10.90; C, 52.39; H, 7.46.

Pharmacological evaluation of 3chloro-4-'(2-diethyl- 20 aminoethoxy) 5 ethoxyaniline hydrochloride according to the procedures referred to in Example 1C has shown that this compound in terms of its free base is approximately nine "times as active a local anesthetic as procaine hydrochloride and about five times as irritating.

EXAMPLE 14 A. 3-Chl0r0-4-(3-Diethylaminopropom -5- Ethoxynitrob nzene This preparation was carried out following the procedure given in Example 1B using 16.1 g. of 2-chloro-4- nitro-6-ethoxyphenol, 16.0 g. of sodium in 370 ml. of ethanol, 1410 ml. of toluene and g. of 3-diethylaminopropyl chloride. Therewas thus obtained 158.5 g. of 3 chloro 4 (3 diethylaminopropoxy) 5 ethoxynitrobenzene as its monohydrochloride salt, M.P. 165.0- 166.2 C. 1(corr.).

Analysis.-Calcd. f0]: C H ClN O .HCl: N i, Cl, 19.31. Found: N 4.05;'Cl, 19.10.

This preparation was carried out following the procedure described in Example 1C using 73.4 g. of 3-chloro-4- (3-diethylaminopropoxy) 5 ethoxynitrobenzene hydrochloride in 800 ml. of a 1:1 mixture of ethanol-water, 67.3 g. of iron powder and 2 ml. of hydrochloric acid in two liters of a 1:1 mixture of ethanol-Water. There was thus obtained 56 g. of 3-chloro-4-(S-diethylaminopropoxy)-5- ethoxyaniline as its monohydrochloride salt, M.P. 147.4-j- 149.4 C. (corn). I

Analysis.'-Calcd. for C H ClN O HCl: C1", 10.51; Cl, 21.02. Found: 01-, 10.50; Cl, 21.30.

The compounds disclosed and claimed in this application are useful not only as local anesthetics but also as intermediates tor the preparation of certain N-lower-acyl derivatives thereof, namely halo-(lower-hydrocarbyloxy)- [lower tertiary amino (polycarbon lower alkoxy1- N-lower-alkanoylanilines, which are disclosed and claimed in our co-pending application Serial No. 788,247, filed October-27, 1958, now US. Patent 3,076,845 (patented February 5, 1963), which is a division of our prior copending application Serial No. 606,796, filed August 29, 1956, now abandoned.

This application is a continuation-in-part of the aforesaid prior co-pending application Serial No. 606,796, filed August 29, 1956, .now abandoned.

Our halo (lower alkoxy) [lower tertiary amino- (polycarbon-lower-hydrocarbyloxy)]-aniline derivatives can be formulated in the manner conventional for local anesthetics. For example, they can be conveniently used as their acid addition salts, e.g., hydrochlorides, in aqueous liquidpreparations. These preparations can be administered topically or injected intramuscularly or intravenously. Our compounds can also be advantageously combined with other pharmacologically active'compounds, e.g., vasoconstrictor agents.

We claim:

1. A compound having the formula (halogen) where R is a member of the group consisting of loweralkyl having from one to eight carbon atoms inclusive and benzyl, X is lower-alkylene having from two to four carbon atoms inclusive and having its two free valence bonds on different carbon atoms and NB is selected from the group consisting of di-(lower-alkyl) amino, l-piperidyl, (lower-alkylated)-l piperidyl, l-pyrrolidyl and (loweralkylated)-1-pyrrolidyl.

RO (halogen) where R is lower-alkyl having from one to eight carbon ,atoms inclusive, X is lower-alkylene having from two to four carbon atoms inclusive and having its two free valence bonds on diiferent carbon atoms, and NB is di-(loweralkyl) amino.

3. 3-br0mo-4-(Z-diethylaminoethoxy)-5-eth0xyaniline.

4. 3 bromo 4 (2 diethylaminoethoxy) n propoxyaniline.

5. 3 bromo 4 (2 diethylaminoethoxy) 5 nbutoxyaniline.

6. 3 bromo 4 (2 diethylaminoethoxy) 5 nhexoxyaniline.

7. 3 bromo 4 (2 diethylaminoethoxy) 5 methoxyaniline.

8. 3 chloro 4 (2 diethylaminoethoxy) 5 methoxyaniline.

9. 3 -chloro 4 (2 dimethylaminoethoxy) 5 methoxyaniline.

10. 3 chloro 4 (3 dimethylaminopropoxy) 5- methoxyaniline.

11. 3 chloro 4 (3 diethylaminopropoxy) 5- methoxyam'line.

12. 3 chloro 4 [2 (2 methyl 1 piperidyl)eth-- 22 15. 3 chloro 4 (3 diethylaminopropoxy) 5- ethoxyaniline.

16. 3 bromo 4 (2 diethylaminoethoxy) 5 benzyloxyaniline.

17. A 3 halo-4-(dialkylaminoalkoxy)-5-benzyloxyaniline having the formula Where X is lower-alkylene having from two to four carbon atoms inclusive and having its two free valence bonds on different carbon atoms, and NB is di-(lower-alkyl) amino.

References Cited in the file of this patent UNITED STATES PATENTS 2,599,000 Kerwin et al. June 3, 1952 2,642,436 Clinton et al June 16, 1953 2,765,338 3 Suter et al. Oct. 2, 1956 2,824,872 Lassauniere Feb. 25, 1958 2,828,313 Scholz et a1. Mar. 25, 1958 FOREIGN PATENTS 500,675 Belgium Feb. 15, 1951 172,651 Austria Oct. 10, 1952 298,415 Switzerland July 1, 1954 742,819 Great Britain Jan. 4, 1956 OTHER REFERENCES Bosshard: Helvetica Chimica Acta, vol. 27, p. 1745 1944.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent N00 3 13s 075 May 12 1964 Raymond 0 Clinton et ale It ishereby certified. that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 3 line 51 for "intermeidates" read intermediates column 4 line 55 for "onct" reed once column 7 line 69 for "-=l-=[-(2 4" read -4--[2-(2,,4 column ll line l5 for "2 nirto read 2-nitro=- -n Signed and sealed this 22nd day of September 1964;

(SEAL) Attest:

ERNEST 121.. SWIDER Q EDWARD J. BRENNER Attesting C finer Commissioner. of Patents 

1. A COMPOUND HAVING THE FORMULA 